Benzodiazepine process

ABSTRACT

(WHEREIN R5 and R6 represent individually a hydrogen atom, a halogen atom, a lower alkyl group or a trifluoromethyl group); R3 is a hydrogen atom or a lower alkyl group; R4 is a lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl group; m is 1 or 2; and n is an integer of 1 to 4, and a process for preparation thereof and pharmaceutical use of the same. The benzodiazepine derivatives are effective as tranquillizers, muscle-relaxants and hypnotics. Novel 1-substituted benzodiazepine derivatives and salt thereof having the formula,   WHEREIN R1 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a lower alkoxy group or a trifluoromethyl group; R2 is a pyridyl group or a group of the formula

United States Patent [191 Yamamoto et al.

[ Feb. 18, 1975 BENZODIAZEPINE PROCESS [73] Assignee: Sumitomo ChemicalCompany,

Limited, Osaka, Japan [22] Filed: Jan.29,1971

21 App1.No.:l11,l41

[30] Foreign Application Priority Data Feb. 3, 1970 Japan 45-9691 Feb.5, 1970 Japan 45-10533 [52] US. Cl. ..260/294.80, 260/326 S, 260/307 B,260/562 N, 424/244, 424/263 [51] Int. Cl C07d 53/06 [58] Field of Search260/2393 D [56] References Cited UNITED STATES PATENTS 3,121,075 2/1964Keller et al. 260/2393 D 3,371,085 2/1968 Reeder et al. 260/2393 D3,391,138 7/1968 Archer et a1 260/2393 D OTHER PUBLICATIONS Sternbach,et al., Some Aspects of Structure-Activity Relationship in PsychotropicAgents of the 1,4Benzodiazepine Series A Symposium Held at the Re gionalResearch Laboratory, Hyderbad, India CSlR New Delhi, India (1966).

Primary Examiner-Henry R. Jiles Assistant Examiner-Robert T. BondAttorney, Agent, or FirmStevens, Davis, Miller & Mosher [57] ABSTRACTNovel l-substituted benzodiazepine derivatives and salt thereof havingthe formula,

wherein R1 is a hydrogen atom, a halogen atom, a nitro group, a cyanogroup, a lower alkoxy group or a trifluoromethyl group; R is a pyridylgroup or a group of the formula (wherein R and R represent individuallya hydrogen atom, a halogen atom, a lower alkyl group or atrifluoromethyl group); R is a hydrogen atom or a lower alkyl group; Ris a lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl group; mis l or 2; and n is an integer of l to 4, and a process for preparationthereof and pharmaceutical use of the same.

The benzodiazepine derivatives are effective as tranquillizers,muscle-relaxants and hypnotics.

4 Claims, No Drawings BENZODIAZEPINE PROCESS This invention relates tonovel l-substituted benzodiazepine derivatives and salts thereof. Moreparticularly, the invention pertains to novel l-substitutedbenzodiazepine derivatives, and salts thereof, represented by thegeneral formula (I),

wherein R is a hydrogen atom, a halogen atom, a nitro group, a cyanogroup, a lower C -C alkoxy group or a trifluoromethyl group; R is apyridyl group, or a group of the formula (where R; and R representindividually a hydrogen atom, a halogen atom, a lower C -C alkyl groupor a trifluoromethyl group); R1, is a hydrogen atom or a lower C -Calkyl group; R is a lower C C, alkyl group, a C,-,-C,,- cycloalkylgroup, a C C cycloalkyl group, a C C cycloalkyl-C C, alkyl group, anaryl group or an aralkyl group, and m is l or 2; and n is an integer ofl to 4, and a process for preparation thereof and pharmaceutical use ofthe same.

In the compounds represented by the aforesaid general formula (I), thehalogen atom includes fluorine, chlorine, bromine and iodine; the alkylgroup includes straight-chain and branched-chain alkyl groups, the loweralkyl group includes, for example, methyl, ethyl, n-propyl, iso-propyl,n-butyl and t-butyl groups; the lower alkoxy group includes, forexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy and t-butoxygroups; the cycloalkyl group includes, for example, cyclopropyl,cyclobutyl, cyclohexyl and cyclopentyl groups; the

The l-substituted benzodiazepine derivatives represented by theaforesaid general formula (l) and salts thereof are novel compounds. Ithas surprisingly been found by the present inventors that the compoundsrepresented by the formula (I), especially the compounds represented bythe formula,

wherein R R R R and m are as defined in the formula (I) above, and nrepresents 2 or 3, and their pharmaceutically acceptable salts withinorganic and organic acids, have valuable pharmacological properties,in particular excellent tranquillizing, sedative, muscle relaxant,spasmolytic and hypnotic activities.

Accordingly, an object of the present invention is to provide novel anduseful benzodiazepines and salts thereof which have excellentpharmacological properties. Another object is to provide a process forproducing such novel and useful benzodiazepines and salts thereof. Afurther object is to provide pharmaceutical composition containing suchnovel and useful benzodiazepines or salts thereof. Othrobjects andmerits of the present invention will be apparent from the followingdescriptions.

In order to accomplish these objects the present invention providesnovel benzodiazepines represented by the formula (I) and acid additionsalts thereof.

According to the present invention, the novel benzodiazepinesrepresented by the formula (I) may be prepared by a variety of methods.

One method for producing the benzodiazepines of the formula (I) whichcomprises reacting lunsubstituted benzodiazepines represented by theformula C N Il -QC c CH R3 (II) wherein R R and R are as defined in theformula (I) above, with a reactive ester of a compound represented bythe formula,

wherein R,, m and n are as defined above. Examples of reactive estersinclude hydrohalic acid esters such as the chlorides, bromides andiodides and sulfonic acid esters such as methanesulfonate,p-toluenesulfonate, B-naphthalenesulfonate andtrichloromethanesulfonate. The reaction may be carried out by reacting acompound of the formula (ll) with a reactive ester of the compound ofthe formula (III) in the presence ofan alkaline agent or by contactingthe compound of the formula (II) with an alkaline agent to form themetal salt and then contacting the resulting metal salt with a reactiveester of the compound of the formula (III). Examples of the alkalineagents include alkali metal hydride such as sodium hydride or lithiumhydride, alkali metal hydroxide such as potassium hydroxide, alkalimetal amide such as sodium amide, potassium amide or lithium amide,alkyl-alkali such as butyl lithium, phenylalkali such as phenyl lithium,alkali metal alcoholate such as sodium methylate, sodium ethylate,potassium tertiary-butoxide or the like. The reaction may generally beeffected in an organic solvent or solvent mixture. Suitable solventsinclude benzene, toluene, xy' lene, dimethylformamide,dimethylacetamide, di-

RH C VH 8(0) R wherein R,, R R,, n and m are as defined in the formula(l) above, with a 2,5-oxazolidinedione having the formula,

(v) m c wherein R is as defined in the formula (l) above. The reactionis carried out in the presence of a solvent or solvent mixture. Suitablesolvent include, for example, chloroform. carbon tetrachloride,methylene chloride, ethylene chloride, ether, diisopropyl ether,tetrahydrofuran, dioxane, water, methanol, ethanol, dimethylformamide,dimethyl sulfoxide or a mixture thereof. The reaction is, generally,carried out in the presence of an acid. The acid used in this processincludes hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoricacid, polyphosphoric acids, borontrifluoride and paratoluenesulfonicacid. The reaction is effected at a temperature ranging from 31 C toabout 120C, and more preferably from about 0C to about C. Temperaturesabove and below the aforesaid ranges can also be employed but are lesspreferred. In most instances, the reaction can be conducted at roomtemperature or below. Pressure is not critical and the process can beconducted at atmospheric, subatmospheric or superatmospheric pressure.The process, if desired, can be conducted in an inert atmosphere, suchas nitrogen, argon and the like.

Although the mole ratio of the 2,5-dione derivative to the aminophenylketone derivative is not critical, it is preferable to use at leaststoichiometric amount of the reactant. In most cases, it is morepreferable to use an excess of the 2,5-dione derivative.

The reactant can be, if necessary, heated in a suitable solvent, such asdimethylsulfoxide, dimethylformamide or the like to complete thereaction.

Yet another method for preparing benzodiazepine derivative of theformula (I) which comprises treating an Laminomethylindole derivative,or an acid addition salt thereof, having the formula,

wherein R R R, and n are as defined in the formula (I) above, and 1represents 0, 1 or 2, with an oxidizing agent. Examples of the acidaddition salt include hydrochloride, hydrobromide, sulfate or phosphate.The oxidizing agent for this process includes, for example, ozone,hydrogen peroxide, peracid (e.g., performic, peracetic and perbenzoicacid), chromic acid and potassium permanganate, but is not limited tothe named compounds. Generally, the reaction progresses readily at roomtemperature, but the temperature may be higher or lower, for example, 0about 100C or a boiling point of the solvents, preferably 10 C, asnecessary to effect the desired control of the reaction, and thereaction temperature varies depending on the oxidizing agent employed.The preferable oxidizing agent is chromic acid or ozone. The reaction ispreferably effected in the presence of a solvent. The choice of solventdepends on the oxidizing agent employed, and is selected from the groupconsisting of water, acetone, carbon tetrachloride, formic acid, aceticacid, sulfuric acid and the like. The oxidizing agent is used in thestoichiometric amount or more.

Where the oxidation is carried out by use of chromic acid in thepresence of acetic acid, it is preferable that the chromic acid may beused in 2 3 times the equimolar amount and the reaction may be carriedout at room temperature. A 2-aminomethylindole derivative is dissolvedor suspended in the solvent and the oxidizing agent is added to thesolution or suspension with stirring.

Where the oxidation is carried out by use of ozone, the reaction ispreferably carried out at room temperature. A 2-aminomethylindolederivative is dissolved or suspended in the solvent such as formic acid,acetic acid, carbon tetrachloride or the like and ozonized oxygen isbubbled into the solution or suspension with stir ring.

The desired benzodiazepine derivative can be separated from the reactionmixture in a crude form by extraction, with or without priorneutralization, and by evaporation to dryness. The product is furtherpurified, if desired, by recrystallization from a suitable solvent suchas ethanol, isopropanol, isopropylether or their mixture or the like ina standard procedure.

Still another method for preparing benzodiazepine derivative of theformula (l-a) which comprises contacting be nzodiazepine derivative orsalt thereof having the formula,

0 FQQ wherein R R R R and n are as detmed m the tormula (l-aabove, and pis zero or l; with an oxidizing agent. As the oxidizing agent, there isused, for exam ple, chromic acid, nitric acid, hydrogen peroxide,organic peracid (e.g., performic, peracetic, perbenzoic orm-chloroperbenzoic acid), sodium periodate, potassiumperiodatepersulfate, selenium dioxide, lead tetracetate, manganesedioxide or ruthenium tetraoxide. The reaction is advantageously effectedin the presence of a solvent, in general. The choice of the solventdepends on the oxidizing agent employed, and is selected from the groupconsisting of water, chloroform, carbon tetrachloride, acetone, aceticacid, formic acid, sulfuric acid, pyridine, dioxane, benzene, toluene,ether, ethyl acetate, methanol, ethanol and the like, and a mixturethereof. The reaction temperature varies depending on the oxidizingagent employed. When it is desired to obtain a compound of the formula(l-9wherein m is l, the reaction is advantageously effected at or belowroom temperature. When it is desired to obtain a compound of the formula(l-a) wherein m is 2, the reaction is advantageously effected at orabove room temperature.

The other method for preparing benzodiazepine of the formula (l-a)whichcomprises treating compound representedby the formula,

is a group of the formula,

and the like. The removal of the protecting system is effected byutilizing conventional procedures well established in the art. Forexample, if Z in the formula (Vlll) represents a phthaloyl group as theprotective group, the system is removed by reacting such compounds withhydrazine derivatives such as hydrazine hydrate or phenylhydrazine,whereby to prepare the objective compound of the formula (l-a). Thereaction is preferably effected in the presence of a solvent or solventmixture. Suitable solvents are, for example, methanol, ethanol,isopropanol, water and the mixture thereof. The reaction is carried outat a temperature within the range between about room temperature and theboiling point of the solvent employed,

If the system Z in the formula (Vlll) consists of a carbobenzoxy groupas the removable group and hydro gen, the removal of the system iseffected by using hydrogen halide. Suitable hydrogen halides includehydrogen bromide and hydrogen chloride. The preferred hydrogen halide ishydrogen bromide. Hydrohalic acid such as hydrobromic acid andhydrochloric acid may be used as the hydrogen halide, such ashydrobromic acid or hydrochloric acid. The reaction is carried out in asolvent or solvent mixture. Suitable solvents are methanol, ethanol,acetic acid, water or the like, or a mixture thereof.

The reaction is carried out at a temperature within the range betweenabout room temperature and the boiling point of the solvent used. Theprocess may either proceed directly to the desired compounds of theformula (1-11) or through intermediates of the formula,

wherein R R R R m and n are as defined above, which may then be cyclizedto the desired compound of the formula (l-a). The intermediate of theformula (IX), ifdesired, may be isolated as the hydrohalides by theselection of mild reaction conditions, such as appropriate reactiontemperature and reaction time. The compound of the formula (lX) may bering-closed to the desired compound of the formula (l-a) by beingallowed to stand at room temperature or at an elevated temperature in asuitable solvent such as acetic acid, methanol, ethanol, pyridine,dimethyl sulfoxide or the like with or without treatment with a base.

According to the process of the present invention, there are obtained,for example, the following compounds:

l-Methylsulfonylmethyl-5-phenyl-7-chloro-l ,3-

dihydro-2H-l ,4-benzodiazepin-2-onel-Methylsulfonylmethyl-5-phenyl-7-nitro-l ,3-

dihyd ro-2H-l ,4-benzodiazepin-2-onel-Methylsulfonylmethyl-5-(o-fluorophenyl)-7- chloro-1,3-dihydro- 2l-l-l,4-benzodiazepin-2-onel-Methylsulfonylmethyl-5-(2'-pyridyl)-7-bromo-1,3-

dihydro-ZH-l ,4-benzodiazepin-2-onel-Ethylsulfonylmethyl-5-phenyl-7-chlorol ,3-

dihydro-ZH- 1 ,4-benzodiazepin-2-one 131-Methylsulfinylmethyl-5-(o-methyl-pchlorophenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-Z-one 1-(B-Ethylsulfinylethyl)-5-(o,o-difluorophenyl)-7-chloro-l ,3-dihydro-2H-1,4-benzodiazepin-2-onel-(B-Ethylsulfinylethyl)-5-(o,o'-dichlorophenyl)-7- chloro-l,3-dihydro-2H-1,4-benzodiazepin-2-one1-(y-Methy1sulfinylpropyl)-5-(o,o'-dichlorophenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-onel-(y-Ethylsulfinylpropyl)-5-(o,o-difluorophenyl)-7- chloro-l,3-dihydro-2H-1,4-benzodiazepin-2-one1-(y-Ethylsulfinylpropyl)-5-(o,o'-dichlorophenyl)-7 chloro-l,3-dihydro-2H-1,4 benzodiazepin-2-one The thus obtained benzodiazepinederivatives of the formula (I) and (La) form pharmaceutically acceptableacid addition salts with pharmaceutically acceptable inorganic andorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid, nitric acid, acetic acid, maleic acid, fumaricacid, tartaric acid, succinic acid, citric acid, camphorsulfonic acid,ethanesulfonic acid, ascorbic acid, lactic acid, and the like.

The benzodiazepine derivatives of the formula (I), especially (l-a) ortheir pharmaceutical acceptable acid addition salts are useful assedatives, muscle relaxant, hypnotics and anticonvulsants.

lllustratively, 1-(B-methylsulfonylethyl)-5-(ofluorophenyl)-7-chloro- 1,3-dihydro-2H-l ,4- benzodiazepin-Z-one and l-(B-methylsulfinylethyl)-5-phenyl-7-chloro-1,3-dihydro-2H-l ,4-benzodiazepin- 2-one showanticonvulsant, muscle relaxant and hexobarbital potentiation activitieswith low toxicy. These pharmacological activities of the presentcompounds are found to be more potent than those ofthe chemical relatedcompounds, Chlorodiazepoxide (2-methylamino-5-phenyl-7-chloro-3H-1,4-benzodiazepin-4-oxide).

Benzodiazepines or salts thereof of the present invention can beadministered parenterally or orally in therapeutic dosage forms withdosage adjusted to individual needs, that is, in solid or liquid dosageforms such as tablets, dragees, capsules, suspensions, solutions,elixirs and the like.

This invention is further illustrated by the following examples ofpreferred embodiments thereof, which are presented for purpose ofillustration and are not intended to limit the scope of the invention.

EXAMPLE 1 A solution of 1 g of 5-phenyl-7-ch1oro-l,3-dihydro-2H-1,4-benzodiazepin-2-one in 15 ml of N,N-dimethylformamide is added toa suspension of 0.3 g sodium methoxide in 15 ml ofN,N-dimethylformamide, and the mixture is heated at 50 60C for 1 hour.After the mixture is cooled, a solution of 2 ml of B-methylsulfinylethylchloride in 10 ml of toluene is added thereto below 10C. The resultingmixture is stirred at room temperature for 30 minutes, and then at 8090C for 5 hours. The reaction mixture is poured into ice water, andextracted with methylene chloride. The methylene chloride extracts arecombined and dried over anhydrous sodium sulfate, and the solvent isremoved under reduced pressure. The residue is allowed to stand to formcrystals. Recrystallization from ethyl acetate givs,l-(,B-methylsulfinylethyl)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one as colorless prisms, m.p. 166 -167C.

EXAMPLE 2 Using the procedure similar to that in Example 1, butreplacing ,G-methylsulfinylethyl chloride by ,B-methylsulfonylethylchloride, there is obtained l-(B-methylsulfonylethyl)-5-phenyl-7-ch1oro-1,3-dihydro- 2H-l,4-benzodiazepin-2-one.

similarly, the following compounds are obtained.

1-Methylsulfonylmethyl-5-phenyl-7-chloro-1,3-

dihydro-2H-1,4-benzodiazepin-2-one, m.p. 163 165C.

1-Methylsulfonylmethyl-5-phenyl-7-nitro-1,3-dihydro-2H-1,4'benzodiazepin-2-one, m.p. 192

EXAMPLE 3 To a solution of 0.5 g of 2-(B-methylsulfonylethyl)amino-S-chlorobenzophenone in 20 ml of dry methylene chloride is added0.5 g of oxazo1idine-2,5-dione. To the mixture is added 20 ml ofethereal hydrogen chloride under cooling. The mixture is stirred at roomtemperature. After completion ofthe reaction, the mixture is poured intoice water, basified with aqueous ammonia and extracted with methylenechloride. The extracts are combined and dried over anhydrous sodiumsulfate, and the solvent is removed under reduced pressure. The residueis added with isopropyl alcohol to form crystals. Recrystallization fromacetone gives 1- (,B-methylsulfonylethyl)-5-phenyl-7-chloro-1,3-dihydro-ZH-l,4-benzodiazepin-2-one as colorless leaflets.

EXAMPLE 4 Using the procedure similar to that in Example 3 but replacingZ-(B-methylsulfonylethyl)amin0-5- chlorobe nzophenonc by 2-( B-methylsulfinylethyl)amino-S-chloro-benzophenone, there is obtainedl-(B-methylsulfinylethyl)5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin2one, m.p. 166 167C.

Similarly, the following compounds are obtained.

1-Methylsulfonylmethyl-5-phenyl-7-chloro-1,3-

dihydro-2H1,4-benzodiazepin-2-one, m.p. 163 165C.

1-Methylsulfonylmethy1-5-phenyl-7-nitro-1,3-dihydro-ZH-l,4-benzodiazepin-2-one, m.p. 192

1-Methylsulfinylmethyl-5-phenyl-7-ch1or0-1,3-

dihydro-2H'1,4-benzodiazepin-2-one, m.p. 158 159C.

l-Methylsulfinylmethyl-5-phenyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-one, m.p.

l-(/3-Methylsulfonylethyl)-5-(o-fluorophenyl)-7- chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one, m.p. 155 156C.

EXAMPLE 5 A solution of 1 g of chromic anhydride in 1 ml of water isadded to a mixture of l g of l-(B- 15methylthioethyl)-2-aminomethyl-3-phenyl-5- chloroindole and 20 ml ofacetic acid. The mixture is stirred overnight at room temperature. Thereaction mixture is poured into ice water, basified with ammonia waterand extracted with methylene chloride. The methylene chloride extractsare combined and dried over anhydrous sodium sulfate, and the solvent isremoved. The residue is dissolved in chloroform and purified byfiltration through silica gel.

Crystals are obtained from the eluate of ethyl acetate.Recrystallization from acetone gives l-(B-methylsulfonylethyl)-5-phenyl-7-chloro- 1 ,3dihydr-2H-1,4-benzodiazepin-2-one.

EXAMPLE 6 Using the procedure similar to that in Example but replacing1-(B-methylthioethyl)-2-aminomethyl-3-phenyl-S-chloroindole byl-(B-methylthioethyU-Z- aminomethyl-3-(o-fluorophenyl-S-chloroindole,there is obtained 1-(,B-methylsulfonylethyl)-5-(ofluoropheny1)-7-chloro- 1 ,3-dihydro-2H-1 ,4- benzodiazepin-2-one, m.p.155 156C.

Similarly, the following compounds are obtained.

1-Methylsulfonylmethyl-5-phenyl-7-chloro-l ,3-

dihydro-ZH-l,4-benzodiazepin-2-one, m.p. 163 165C.

1-Methylsulfonylmethyl-5-phenyl-7-nitro-1,3-dihydro-Zl-l-l,4-benzodiazepin-2-one, m.p. 192

tained 1-( B-methylsulfonylethyl )-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one, 218 219C.

Similarly, the following compounds are obtained.

1-(B-Methy1sulfony1ethyl)-5-(o-flu0rophenyl)-7-chloro-l,3-dihydro-2H-1,4-benzodiazepin-2-one, m.p. 155 156C.

l-Methylsulfonylmethyl-5-phenyl-7-chloro-1,3-

dihydro-ZH-l,4-benzodiazepin-2-one, m.p. 163 165C.

1-Methylsulfonylmethyl-5-phenyl-7-nitro-1,3-dihydro-ZH-l,4-benzodiazepin-2-one, m.p. 192

EXAMPLE 8 A solution of 10 ml of percent aqueous hydrogen peroxide isadded with ice-cooling to a mixture of 1.5 g of1-(B-methylthioethyl)-5-phenyl-7-chloro-1,3-dihydro-ZH-l,4-benzodiazepin-2-one and ml of acetic acid. The resultantmixture is stirred at 0C for minutes and then at room temperature for 1hour. The reaction mixture is poured into ice water, basified withammonia water and extracted with chloroform. The chloroform extracts arecombined, dried over anhydrous sodium sulfate, and the solvent isremoved under reduced pressure. The residue is allowed to stand to formcrystals. Recrystallization from ethylacetate givesl-(,B-methylsulfinylethyl)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one, m.p. 167C.

EXAMPLE 9 Using the procedure similar to that in Example 9, butreplacing1-(B-methylthioethyl)-5-phenyl-7-chlorol,3-dihydro-2H-1,4-benzodiazepin-2-oneby l-(B- methylthioethyl )-5-(o-fluorophenyl )-7-ch1orol .3-dihydro-2H-1,4-benzodiazepin-2-one, there is obtained1-(B-methylsulfonylethy1)-5-(o-f1uorophenyl)-7-chloro-1,3-dihydro-2H-l,4-benzodiazepin-2-one, m.p. 156C.

EXAMPLE 10 Using the procedure similar to that in Example 9, butreplacing l (B-methylthioethyl)-5-pheny1-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one by 1-( B-methylsulfinylethyl)-5-pheny1-7-chl0ro-1,3-dihydro-2H-1,4-benzodiazepin-2-one, there is obtained l-(B-methylsulfonylethyl)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one, m.p. 218 219C.

Similarly, the following compound is obtained.

1-(B-Methylsulfonylethyl)-5-(o-fluorophenyl)-7-chloro-l,3-dihydro-2H-1,4-benzodiazepin-2-one, m.p. 155 156C.

EXAMPLE 11 A mixture of 1 g of 2-[N -(B-methylsulfonylethyU- N-(N-carbobenzoxyglycy1)amido]-5-chlorobenzophenone and 20 m1 of 30 percenthydrogen bromide-acetic acid is stirred at room temperature. Thereaction mixture is poured into water, basified with ammonia water andextracted with methylene chloride. The methylene chloride extracts arecombined and dried over anhydrous sodium sulfate, and the solvent isremoved. The residue is crystallized from isopropyl a1- cohol to give1-([3-methylsulf0nylethyl)-5-phenyl-7-chloro-l,3-dihydro-2H-1,4-benzodiazepin-2-one, which is recrystallizedfrom acetone, m.p. 160

Similarly, using the above procedure but replacing2-[N-(B-methylsulfonylethyl)-N'-(Ncarbobenzoxyglycyl)amidol-5-chloro-benzophenone by2-[N(B-methylsulfonylethyl)-N'-(Ncarbobenzoxygylcyl)amidol-5-chloro-2'-fluorobenzophenone, there isobtained 1-(B- methylsulfonylethyl)-5-(o-fluorophenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one, m.p. 155 156C.

Similarly, the following compound is obtained.

1-(B-Methylsulfinylethyl)-5-phenyl-7-chloro-1,3-dihydro-2H-l,4-benzodiazepin-2-one, m.p. 166 167C.

EXAMPLE 12 To a mixture of 1 g of 2-(N-phtalimidoacetyl-N-B-methylsulfonylethyl)amino-S-chloro-Z'-fluorobenzophenone, 15 ml ofmethylene chloride and 15 ml of ethanol is added a solution of 2 g ofhydrazine hydrate in 2 ml of water. The mixture is stirred at roomtemperature. The reaction mixture is concentrated under reducedpressure, diluted with water, basified with ammonia water and extractedwith ether. The ethereal layers are combined and dried over anhydroussodium sulfate and the solvent is removed. The residue is crystallizedfrom a small amount of isopropyl ether to give1-(B-methylsulfonylethyl)-5-(o-fluorophenyl)- 7-chl0ro l ,3-dihydro-2H-l,4-benzodiazepin-2-one.

Recrystallization from isopropylethermethylene chloride gives colorlessprisms, m.p. 155 156C.

Similarly, the following compounds are obtained.

l-(B-Methylsulfonylethyl)--phenyl-7-chloro-1,3-dihydro-ZH-l,4-benzodiazepin-2-one, m.p. 160 161C.

l-(B-Methylsulfinylethyl)-5-phenyl-7-chloro-1,3- dihydro-2H- l,4-benzodiazepin-2-one, m.p. 167C.

What is claimed is:

l. A process for preparing benzodiazepine derivatives and salts thereofwhich comprises reacting in the presence of a solvent and in thepresence of an acidic catalyst an aminophenylketone derivative havingthe formula.

formula where R and R represent individually a hydrogen atom, a halogenatom, a C C alkyl group or a trifluoromethyl group); R is a C C alkylgroup; m is 1 or 2; and n is an integer of l to 4, with a 2,5-oxazolidinedione having the formula,

wherein R is a hydrogen atom or a C, C alkyl group, wherein the reactionis carried out at a temperature ranging from -25C to +C and wherein atleast one mole of the 2,5-dione derivative is used per mole of theaminophcnylketone derivative.

2. A process according to claim 1, wherein the acid is selected from thegroup consisting of hydrogen chloride, hydrogen bromide, sulfuric acid,polyphosphoric acid phosphoric acid, boron trifluoride andp-toluencsulfonic acid.

3. A process according to claim 1, wherein the solvent is selected fromthe group consisting of chloroform, carbon tetrachloride, methylenechloride. ethylene chloride, diethyl ether, diisopropyl ether.tetrahydrofuran, dioxane, water, methanol, ethanol, dimcthylformamide ordimethyl sulfoxide.

4. A process according to claim 1, wherein the reaction is carried outat a temperature ranging from 0C to 30C.

UNITED STATES PATENT OFFICE (IERTEFICATE 0F CORRECTION Patent No. 3,3 7x72 Dated Eeb. 18, 197';

Inventor(s) Hisao Yamamoto, et a1 It is certified that error appears inthe above-identified patent and that said Letters Patent are herebycorrected as shown below:

The term of this patent subsequent to December 11, 1990 has beendisclaimed.

Signed and Scaled this Seventeenth Day Of August 1976 [SEAL] A ttest:

mm: c. MASON c. MARSHALL DANN 14119811718 ff Commissioner ofPatents andTrademarks

1. A PROCESS FOR PREPARING BENZODIAZEPINE DERIVATIVES AND SALTS THEREOFWHICH COMPRISES REACTING IN THE PRESENCE OF A SOLVENT AND IN THEPRESENCE OF AN ACIDIC CATALYST AN AMINOPHENYLKETONE DERIVATIVE HAVINGTHE FORMULA,
 2. A process according to claim 1, wherein the acid isselected from the group consisting of hydrogen chloride, hydrogenbromide, sulfuric acid, polyphosphoric acid phosphoric acid, borontrifluoride and p-toluene-sulfonic acid.
 3. A process according to claim1, wherein the solvent is selected from the group consisting ofchloroform, carbon tetrachloride, methylene chloride, ethylene chloride,diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, water,methanol, ethanol, dimethylformamide or dimethyl sulfoxide.
 4. A processaccording to claim 1, wherein the reaction is carried out at atemperature ranging from 0*C to 30*C.